Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder caused by mutations in the survival motor neuron 1 gene (SMN1) significantly reducing SMN protein expression (Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene, Cell 80, 155-165, 1995; Coovert, D. D. et al. The survival motor neuron protein in spinal muscular atrophy Hum. Mol. Genet. 6, 1205-1214, 1997) and resulting in the selective degeneration of lower a-motor neurons (Crawford, T. O. & Pardo, C. A. The neurobiology of childhood spinal muscular atrophy, Neurobiol. Dis. 3, 97-110, 1996). Clinically, patients with SMA 1 typically show symptoms at 6 months of age and die by age 2 (Munsat, T. L. & Davies, K. E. International SMA consortium meeting, 26-28 Jun. 1992, Bonn, Germany, Neuromuscul. Disord. 2, 423-428, 1992).
The SMN2 gene is almost identical to SMN1 except that SMN2 has a single nucleotide difference that results in only 10% of the full-length protein being produced and high levels of a truncated, unstable protein lacking exon 7 (SMND7). However, patients with several copies of SMN2 produce more full-length protein and have a less severe phenotype.
The nomenclature “SMA Type 1” is related to the copy number of SMN2 gene. All SMA patients have 100% knock-down of the SMN1 gene. A copy of the gene that only produces 10% normal protein is a modifier gene. Children with only one copy of the SMN2 gene have the most severe form of the disease (Type 1 SMA). (Children with no copies of the SMN2 gene do not survive.) As the copy number of the SMN2 gene increases, the severity of the disease decreases because the patient has more functional SMN protein. In general, SMA Type II patients typically have two copies of the SMN2 gene and Type III and IV have three and four copies respectively of the gene, although this is not absolute.
Although current model systems using worms, flies or mice have provided invaluable data concerning the genetic cause of SMA, the mechanisms of motor neuron death and potential drug therapies (Schmid, A. & DiDonato, C. J. Animal models of spinal muscular atrophy J. Child Neurol. 22, 1004-1012, 2007), they have important limitations. For example, mice, flies and worms lack the SMN2 gene and, thus, animal models require complicated knockout and over-expression strategies (Schrank, B. et al., Proc. Natl Acad. Sci. USA 94, 9920-9925, 1997; DiDonato, C. J. et al., Genome Res. 7, 339-352, 1997; Hsieh-Li, H. M. et al., Nature Genet. 24, 66-70, 2000; Monani, U. R. et al., Hum. Mol. Genet. 9, 333-339, 2000; Le, T. T. et al. SMNΔ7, gene, Hum. Mol. Genet. 14, 845-857, 2005).
As some therapies aim to target activation of endogenous SMN2 as a potential disease modifier, a human cell-based assay system would be very beneficial. Although SMA patient fibroblasts are available for study, fibroblasts do not show the same vulnerability as motor neurons, and the processing and functioning of the SMN protein probably has unique features in a neural context that is highly relevant for understanding disease mechanisms.
Induced pluripotent stem (iPS) cells, which show marked similarities to embryonic stem cells, can now be derived from human adult somatic tissues (Park, I. H. et al., Nature 451, 141-146, 2008; Jaenisch, R. & Young, R., Cell 132, 567-582, 2008; Takahashi, K. et al., Cell 131, 861-872, 2007; Yu, J. et al., Science 318, 1917-1920, 2007; Lowry, W. E. et al., Proc. Natl. Acad. Sci. USA 105, 2883-2888, 2008), and recent studies have been successful in generating patient-specific iPS cells from a variety of diseases including amyotrophic lateral sclerosis, muscular dystrophy and Huntington's disease (Dimos, J. T. et al., Science 321, 1218-1221, 2008; Park, I. H. et al., Cell 134, 877-886, 2008). None of these reports, however, has shown any disease-specific changes in cell survival or function.